Favorable Clinical Response Research Articles

Early response to the treatment of choroidal neovascularization complicating central serous chorioretinopathy: a OCT-angiography study.

To analyze the quantitative and qualitative early changes of choroidal neovascularization (CNV) associated with chronic central serous chorioretinopathy (CSC) after treatment using optical coherence tomography-angiography (OCT-A). Charts of consecutive patients with diagnosis of chronic CSC complicated by CNV were retrospectively reviewed. Included patients were divided in photodynamic therapy (PDT) or aflibercept group on the basis of the treatment received (half-fluence PDT or aflibercept 2.0 mg/0.05 ml intravitreal injection). Main outcome measures included the changes between baseline and 1-month follow-up in CNV vessel density (VD) and area on OCT-A images after thresholding and binarization. A total of 30 eyes of 26 Caucasian patients were included: 17 eyes of 15 patients in PDT group (mean age 53 ± 11 years) and 13 eyes of 11 patients in aflibercept group (mean age 58 ± 8 years [p = 0.196]). In both PDT and aflibercept groups, best-corrected visual acuity improved at 1 month, and central macular thickness and subretinal fluid significantly decreased. VD did not change after the treatment in both groups (p = 0.502 and p = 0.086) although CNV area decreased significantly (from 0.586 ± 0.449 mm2 to 0.553 ± 0.453 mm2 [0.041]) in the PDT group, and nonsignificantly (from 0.767 ± 0.466 mm2 to 0.733 ± 0.472 mm2 [p = 0.095]) in the aflibercept group. The same results were confirmed in the subanalysis of the 18 treatment-naïve eyes. We demonstrated that, despite all patients showed a favorable clinical response, VD of CNVs complicating chronic CSC did not change after treatment. These findings support the idea that arteriogenesis is the main driving force of CNV in pachychoroid-related macular disorders.

Abstract CT237: Evaluation of in vivo chimeric antigen receptor (CAR) transgene levels in patients (pts) treated with tisagenlecleucel

Abstract Background: Following infusion of tisagenlecleucel, quantitative polymerase chain reaction (qPCR) can be used to measure in vivo kinetics of CAR transgene. The utility of qPCR to inform individual pt treatment decisions and measure functional persistence is an active area of research. Objective: To determine if CAR transgene detection by qPCR can be used to inform treatment decisions. Methods: Transgene levels in blood measured by qPCR from pivotal phase II studies in pts with relapsed/refractory pediatric and young adult acute lymphoblastic leukemia (pALL; ELIANA [NCT02435849, N=75] and ENSIGN [NCT02228096, N=29]) and adult diffuse large B-cell lymphoma (DLBCL; JULIET [NCT02445248, N=93]) were used to investigate the relationship between transgene persistence and clinical response. Results: In both pALL and DLBCL, there were detectable CAR transgene levels by qPCR in both responders and nonresponders. The geometric mean maximal expansion (Cmax) was similar between responding and nonresponding DLBCL pts, while a 1.7-fold difference was observed in pALL pts. For both DLBCL and pALL, high inter-individual variability in transgene levels was noted. Similarly, higher CAR-T cell expansion from flow cytometry data pooled from responding pALL and pediatric chronic lymphocytic leukemia pts was observed vs nonresponding pts (Mueller KT, et al. Blood 2017), while the levels in DLBCL pts were comparatively lower in blood, likely due to partitioning of functional CAR-T cells to target sites including lymph nodes. The median time to maximal transgene level (Tmax) ranged from 9-10 days in DLBCL responders and nonresponders and pALL responders, while nonresponding pALL pts showed delayed expansion with median Tmax of 20 days. The median time corresponding to last quantifiable transgene level (Tlast) and the half-life estimated from the terminal slope of the cellular kinetic profile, two indicators of persistence, were higher in responding vs nonresponding pts with DLBCL and pALL. Despite this general trend, in some cases, transgene levels were not detectable at later time points in pts with continued response. Although the majority of responding pts show persistent transgene levels, some pts maintained a favorable clinical response despite a decline in transgene levels to below the level of quantification. Conclusion: In both pALL and DLBCL, CAR transgene is initially detected at high levels with high variability in both responders and nonresponders. While the majority of responding pts tend to have persistent transgene levels, some pts maintain favorable clinical responses despite a lack of quantifiable transgene. These results indicate that transgene levels in peripheral blood are not definitive to guide clinical decisions in pALL and DLBCL. Further analysis is needed to understand how CAR transgene levels relate to disease burden and duration of response. Citation Format: Rakesh Awasthi, Karen Thudium Mueller, Gregory A. Yanik, Constantine S. Tam, Susana Rives, Joseph P. McGuirk, Michael A. Pulsipher, Michael W. Boyer, Ulrich Jaeger, Andre Baruchel, Gary D. Myers, Peter Borchmann, Stephen J. Schuster, Heather Stefanski, Michael Bishop, Edward R. Waldron, Ozlem Anak, Abhijit Chakraborty, Eric Bleickardt, Stephane Wong, Lida Bubuteishvili Pacaud, Edmund K. Waller, Shannon L. Maude. Evaluation of in vivo chimeric antigen receptor (CAR) transgene levels in patients (pts) treated with tisagenlecleucel [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT237.

Molecular prediction of chronic myeloid leukemia risk and resistance to imatinib.

e18543 Background: Chronic myeloid leukemia (CML) is characterized by the Bcr-Abl genetic translocation which leads to constitutive tyrosine kinase signaling. Treatment with tyrosine kinase inhibitors as imatinib eliminates CML cells, but resistance often occurs. No specific molecular risk factors or imatinib-resistance predictors have been validated so far, thus the aim of this study was to determine genetic factors that would allow for a better management of this disease. Methods: An age and gender matched case-control study of 57 CML patients and 63 healthy controls was performed. In vitro experiments were performed on K562 cells and an imatinib-resistant K562R cell line. CML patients were treated with imatinib and stratified into responders (complete molecular response after three months, CMR) and non-responders. RNA was isolated from blood leukocytes or cells and used for cDNA synthesis. Gene expression levels were evaluated by real-time PCR and the results analyzed using the delta-delta-Ct method. Differences in expression levels and their prognostic/predictive potentials were evaluated by t-test, linear regression analysis and receiver operating characteristics curve, with statistical significance set at p < 0.05. Results: In CML patients, the Bcl2 and IGF-1R mRNA expression level were higher than in controls (1.03 ± 0.06 vs. 0.92 ± 0.18, p < 0.0001; 1.14 ± 0.15 vs. 1.03 ± 0.15, p = 0.0001, respectively). Prior to treatment, the Bcl2 mRNA levels were lower for the K562 than for the resistant K562R cell line (1.13±0.04 vs. 1.62±0.01, p < 0.0001), and the same was observed for IGF-1R (1.22±0.01 vs. 1.29±0.01, p = 0.001). Patients who achieved a CMR after imatinib treatment had significantly lower pre-treatment levels of Bcl-2 and IGF-1R (0.99 ± 0.05 vs. 1.04 ± 0.06, p = 0.005; 1.12 ± 0.02 vs. 1.15 ± 0.04, p = 0.0123, respectively) compared to patients who did not achieve a CMR, which confirmed the in vitro observed data. Conclusions: High levels of Bcl-2 and IGF-1R mRNA were detected in CML patients, and the analysis of their expression might be used as a low-cost CML screening tool. Successful imatinib treatment was correlated with significantly lower pre-treatment Bcl-2 and IGF-1R levels in vitro and in vivo, which might also be used as a low-cost molecular predictor of a favorable clinical response .

Recombinant humanized anti-PD-1 monoclonal antibody (JS001) in patients with refractory/metastatic nasopharyngeal carcinoma: Interim results of an open-label phase II clinical study.

6017 Background: Metastatic nasopharyngeal cancer (NPC) patients progressed afterstandardtherapy have limited treatment options. Toripalimab, also known as JS001, a humanized IgG4 antibody specific for human PD-1, has been approved for 2nd line treatment of metastatic melanoma in China. Here we report the results from a phase IIstudy in metastatic NPC patients treated with toripalimab.(Clinical trial ID: NCT02915432). Methods: This multi-center, open-label, phase II registration study is designed to evaluate the safety and efficacy of toripalimab in metastaticNPC patients who have failed systemic treatment. Toripalimabis given at 3 mg/kg IV Q2W until disease progression or intolerable toxicity.Tumor PD-L1 expression, plasma EBV DNA level and other biomarkerswill be correlatedwith clinical response. Results: Enrollment of 190chemo-refractory metastatic NPCpatients was completed by Feb 2019 from 17 participating centers. The median age was 46 years, with 89.5% patients received at least 2 lines of prior systemic therapies. Treatment related adverse events (TRAE)occurred in 92% patients, which were mostly grade 1 or 2.Common TRAE includedanemia, hypothyroidism, AST increased, proteinuria, pyrexia, cough, constipation, ALT increased, hypoalbuminemia and pruritus.Grade 3 or higherTRAEoccurred in 25% patients.By the cut-off date of Jan 7 2019, among 135 evaluable patients, 3 complete responses, 31 partial responses and 40 stable diseaseswere observed for an objective response rate (ORR) of 25.2% and a disease control rate of 54.8%. PD-L1 expression results were obtained from 125 patients and 45.6% (57/125) were PD-L1+.PD-L1+ patientsachieved slightly higherORR than PD-L1- patients, 29.8% versus 22.1%. In addition, an average drop of 47-fold plasma EBV DNA copy number was observed in responding patients, which typically proceeded the radiographic identification of clinical benefit. Conclusions: Toripalimab has demonstrated a manageable safety profileand encouraging clinical activity in the largest check-point blockade study in NPC to date. A change in plasma EBV DNA copy number might serve as a predictive marker for favorable clinical response. Patients will be continuously monitored for additional safety and survival readouts. Clinical trial information: NCT02915432.

Use of highly characterized EBV-Specific T Cells outside of the immediate Post-Transplant setting

Background & Aim Given the efficacy of donor-derived EBV-specific T cells (EBVSTs) in the post- HSCT environment, and considering many lymphoma patients are immunocompromised, we hypothesized that third-party EBVSTs can effectively treat EBV+ lymphoma by directly killing lymphoma cells, and by reactivating endogenous immunity. To test this hypothesis, we designed a Phase 1 dose escalation trial (in accordance with regulatory agencies) of third party EBVSTs in patients with relapsed/refractory EBV+ lymphoma. Methods, Results & Conclusion We generated a bank of EBVSTs from eligible donors with diverse HLA haplotypes and highest antigen specificity to the EBV Type 2 latency antigens (LMP1/2, EBNA1, BARF1) using IFNγ ELIspot assay. We constructed a database containing the HLA restriction of antigen specificity for each line to ensure we only choose lines with antigen-specific activity restricted by alleles shared between donor and recipient. We identified a suitable partially matched line for 94% of referred patients within 2 days. We have treated 19 patients, 14 of which are evaluable. At the initial response evaluation timepoint, 8 of these 14 patients had a clinical response (complete, partial, or mixed responses), which was sustained for at least 6 months in 5 patients. Additionally, 4/14 patients experienced prolonged stable disease, despite previous refractory status. Infusions were safe, with no occurrences of graft-versus host disease or cytokine release syndrome. We observed enhanced and sustained viral and non-viral tumor antigen recognition in most responding patients, and early loss of antigen recognition in the 2 patients with progressive disease. Using technology from Adaptive Biotechnologies, we tracked the frequency of patient and line-specific clones at post-infusion timepoints in a subset of patients. While this analysis is still ongoing, early anaylsis indicates that some patients with favorable clinical responses had EBVST clones from the infused line that were identified at both early and late time points. Expansion corresponded with increased responses to EBV or tumor-associated antigens on ELIspot assays, suggesting EBVSTs may act as a “vaccine” for functional clones. We are exploring strategies to enhance persistence and antitumor activity, including lymphodepleting chemotherapy and engineering our T cells resistant to alloreactive rejection. Given the promising responses, we have recently extended our therapy to other EBV+ malignancies.

Influence of age on the clinical efficacy of tigecycline in severely ill patients.

The aim of this study was to define the relationship between age and response to tigecycline among patients treated for complicated skin and soft-tissue infections (cSSTIs) and complicated intra-abdominal infections (cIAIs). Pooled data derived from five European observational studies on the use of tigecycline (July 2006-October 2011), either as monotherapy or in combination with other antibiotics, for the treatment of cSSTI or cIAI were used in the analysis. The total population (N=1782 patients) was divided into three age categories: <65 years (804 patients); 65-80 years (836 patients) and >80 years (139 patients) (data unknown/missing for 3 patients). The overall mean Acute Physiology and Chronic Health Evaluation (APACHE) II score for patients with cSSTI and cIAI was 15.0±7.9 and 16.9±7.6, respectively, and the overall mean Sequential Organ Failure Assessment (SOFA) score was 5.8±3.9 and 7.0±4.2, respectively. Overall, patients with cSSTI and cIAI in the three age groups showed a good response to tigecycline treatment (76.2-80.0% and 69.2-81.1%, respectively) with patients aged ≤80 years showing higher response rates. Patients with cIAI appeared to be at greater risk for all types of adverse events compared with those with cSSTI, particularly in the older age groups. In these real-life studies, tigecycline, either alone or in combination, achieved favourable clinical response rates in all age categories of patients with cSSTIs and cIAIs with a high severity of illness.

A Phase 3 Study of Remestemcel-L versus Placebo Added to Second Line Therapy in Patients with Steroid Refractory Acute Graft Versus Host Disease

Background: Uncontrolled studies have suggested that bone marrow-derived mesenchymal stem cells (MSC) may be effective against acute graft-versus-host disease (aGvHD). We conducted a multicenter, randomized study to assess the efficacy, safety, and clinical benefit of using ex vivo cultured adult human MSC (remestemcel-L) in addition to second-line therapy to treat steroid refractory aGvHD (NCT00366145). Methods: Two-hundred sixty patients, 6 months to 70 years of age, were enrolled from August 2006 to May 2009, and were randomized 2:1 to receive 8 intravenous infusions of remestemcel-L or placebo, given over 4 weeks, in addition to second-line therapy according to institutional standards. Four additional infusions over 4 weeks were indicated for patients with incomplete response at Day 28. Randomization was stratified by aGVHD grade. Efficacy and safety were assessed through 180 days of follow-up, with the primary endpoint being durable complete response (DCR), defined as complete resolution of aGvHD symptoms for any period of at least 28 days after beginning treatment. Findings: Remestemcel-L did not meet the primary endpoint of greater DCR in the intent-to-treat population (35% vs. 30%; p=0.42). In post-hoc analyses patients with liver involvement who received at least one infusion, remestemcel-L had a higher DCR than those who received placebo (29% vs. 5%; p=0.047), and remestemcel-L produced favorable overall complete or partial response (OR) rates at day 28 compared to placebo among patients with liver involvement (55% vs. 26%; p=0.05), and among pediatric patients (64% vs. 23%; p=0.05). Infusions were well-tolerated and similar rates of adverse events were observed between treatment groups. Interpretation: Remestemcel-L was safe and well-tolerated. Results of this study did not demonstrate superior DCR compared to placebo when added to standard of care. The favorable clinical responses seen in some patient subsets may warrant further investigation. Funding: Mesoblast, Inc. (previous sponsor Osiris Therapeutics). Declaration of interest: AD, JU, DIM, EKW, and ES have nothing to disclose. RS has received consultancy fees from Gilead, Merck, and Astellas, served on board of directors for Kiadis, and DSMB of Juno/Celegene. PJM received consultancy fees from Enlivex Therapeutics, Genentech, and Grafalon, and served on DSMB for Pfizer. PK received consultancy fees from Jazz Pharmaceuticals. DS, EB and JH are employees of Mesoblast, Inc. Ethical Approval: The study protocol, all study protocol amendments, the written study patient information, written informed consent forms, and all other appropriate study-related information were reviewed and approved by an Independent ethics Committee (IEC) or Institutional Review Board (IRB) at each study site.

Predictors of Survival to Discharge and Ventricular Recovery after VA-ECMO Support for Acute Myocardial Infarction Complicated by Cardiogenic Shock

Purpose The use of veno-arterial extra-corporeal membrane oxygenation (VA-ECMO) following acute myocardial infarction (AMI) with cardiogenic shock (CS) is increasing, but the ability to predict favorable clinical response is limited. We investigated predictors of in hospital mortality and ventricular recovery in patients supported with VA-ECMO for AMI-CS. Methods We retrospectively reviewed charts of patients with AMI who were supported with VA-ECMO from 2007-2018. Data collected included AMI characteristics and measures of cardiac function. Logistic regression was used to identify predictors of survival to discharge and recovery which was defined as survival to discharge without heart replacement therapy (HRT, durable LVAD or transplant). Results 137 patients were treated with VA-ECMO for AMI during the study period. Mean cardiac index at implantation in the cohort was 1.82 ±0.53 and 26 patients (18.9%) had VA-ECMO placed during active CPR. 43 patients (31.4%) were supported with IABP either before or during VA-ECMO support; 75 patients (54.7%) were supported with Impella either before or during VA-ECMO support. 30-day survival was 60.6% and 52.6% survived to discharge. Of the 72 patients surviving to discharge, 26 (36.1%) were discharged with HRT and 46 (63.9%) had recovery. In a multivariable analysis including, age, gender, lactate, TIMI 3 flow in culprit artery, and LV ejection fraction, younger age was the only independent predictor of survival to discharge (OR 1.18, p=0.02). Independent predictors of ventricular recovery were presence of TIMI 3 flow in culprit artery (OR 5.45, p=0.03) and residual CAD (OR 0.22, p=0.04, Table). At a median follow-up of 375 days (IQR 112, 959) after discharge, 2/46 (4.3%) patients required HRT. Conclusion In patients supported with VA-ECMO for AMI-CS, younger age was associated with survival to discharge while markers of successful revascularization were associated with ventricular recovery.

Abstract P4-14-07: Neoadjuvant exemestane or exemestane plus docetaxel and cyclophosphamide tailored by clinicopathological response to 8–12 weeks' exemestane exposure for ER+/HER2– postmenopausal breast cancer patients

Abstract Aim To investigate the efficacy and safety of initial neoadjuvant endocrine therapy with exemestane (EXE) alone followed by tailored treatment: continued EXE monotherapy for responders or EXE plus docetaxel–cyclophosphamide (TC) combination therapy for non-responders. Methods This open-label phase II study enrolled postmenopausal patients with primary invasive estrogen receptor (ER)-positive, HER2-negative, stage I–IIIA (T1c–T3 N0–2 M0) breast cancer and Ki67 index ≤30%. Patients first received EXE 25 mg/day for 12 weeks. Based on clinical response and change in Ki67 index, responders were defined as patients who achieved complete response (CR), partial response (PR) with Ki67 index ≤5% after treatment, or stable disease (SD) with Ki67 index ≤5% both before and after treatment. Non-responders were defined as patients with PR and Ki67 index &amp;gt;5% after treatment, or SD and Ki67 index &amp;gt;5% before or after treatment. For the subsequent 12 weeks, responders continued EXE monotherapy (continued EXE group) and non-responders received EXE plus 4 cycles of TC (docetaxel 75 mg/m2 and cyclophosphamide 600 mg/m2 every 3 weeks) (EXE+TC group). Primary endpoint was clinical response (CR and PR) at week 24. Results A total of 58 patients (median age 60 years, range 53–67 years) were enrolled between December 2010 and May 2016. Five patients discontinued treatment in the initial 12-week EXE monotherapy period; therefore 53 received the subsequent treatment. After 8–12 weeks of initial EXE monotherapy, 15 patients were classified as responders (8 with PR and Ki67 index ≤5% after treatment, 7 with SD and Ki67 index ≤5% before and after treatment) and 38 as non-responders (5 with PR and Ki67 index &amp;gt;5% after treatment, 33 with SD and Ki67 index &amp;gt;5% before or after treatment). Clinical response rates at weeks 12 and 24 were 71% (10/14, 95%CI 41.9–91.6%) and 57% (8/14, 95%CI 28.9–82.3%), respectively, in the continued EXE group, and 16% (4/25, 95%CI 4.5–36.1%) and 56% (14/25, 95%CI 34.9–75.6%), respectively, in the EXE+TC group. At week 24, no significant difference was found in median Ki67 index between the continued EXE and EXE+TC groups (1.4% and 2.0%, respectively). The proportion of patients with preoperative endocrine prognostic index (PEPI) 0 was higher in the continued EXE than in the EXE+TC group (60% vs 29%), but not significantly so (P=0.058, Fisher's exact test). The breast-conserving surgery rate was 93% and 56% (continued EXE and EXE+TC groups, respectively). Adverse events (AEs) ≥grade 3 were reported in 40% (21/53) of patients (continued EXE group 8%, 1/15; EXE+TC group 53%, 20/38). The most common AEs were leukopenia (37%, 14/38), neutropenia (32%, 12/38), and febrile neutropenia (16%, 6/38) during chemotherapy (EXE+TC group). Conclusion Tailored treatment maintained the favorable clinical response to EXE alone in responders and improved subsequent clinical response in non-responders. EXE+TC was associated with higher incidence of hematological AEs, but these were manageable. The results show the effectiveness of tailored neoadjuvant endocrine and chemoendocrine therapy in postmenopausal ER-positive breast cancer patients. (JBCRG-11TC; UMIN000004752) Citation Format: Yasojima H, Sato N, Masuda N, Morimoto T, Ueno T, Kanbayashi C, Kaneko K, Saji S, Sasano H, Morita S, Ohno S, Toi M. Neoadjuvant exemestane or exemestane plus docetaxel and cyclophosphamide tailored by clinicopathological response to 8–12 weeks' exemestane exposure for ER+/HER2– postmenopausal breast cancer patients [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-14-07.

Abstract #133: Quantitative Differences in White Matter Connections of DBS contacts and Clinical Outcome in Parkinson Disease

Introduction: Surgical planning and post-operative programming of deep brain stimulation (DBS) for Parkinson disease (PD) with motor fluctuations has changed relatively little over the past two decades and relies heavily on microelectrode recording and trial-and-error settings, respectively. Using probabilistic Diffused Tension Imaging (DTI) tractography followed by scheletonization and Tract-based spatial statistics (TBSS) we identified the connections of DBS leads in individual patients who underwent DBS surgery for Parkinson disease. We use these connections and clinical outcome data to predict characteristics associated with a favorable and unfavorable clinical response.

Biological therapies and their clinical impact in the treatment of systemic lupus erythematosus.

The development of biological therapies has had an impact on the management of several medical conditions. Their use in systemic lupus erythematosus (SLE), however, remains very limited. This review has summarized the evidence on the clinical effect of biologicals in SLE. Biological drugs with a number of targets have been studied in several phase II and III randomized controlled trials (RCTs). Positive results have been obtained in phase III RCTs with belimumab and this led to its license for active SLE. The clinical experience with belimumab has confirmed the efficacy and safety of belimumab in SLE. Promising results have been noted in phase II trials for blisibimod, sifalimumab, anifrolumab, and ustekinumab. Despite the fact that the RCTs with rituximab did not achieve their primary endpoint, clinical experience with rituximab is extensive and shows favorable clinical response in refractory renal and non-renal SLE. It is hoped that further ongoing phase III RCTs on a number of biological agents in SLE will highlight the potential role of other biologicals in the management of this challenging and heterogeneous condition.

Staphylococcus lugdunensis endophthalmitis following dexamethasone intravitreal implant

We present a unique case of endophthalmitis with Staphylococcus lugdunensis following dexamethasone intravitreal implant for branch retinal vein occlusion associated with cystoid macular edema. Patient did not show favorable clinical response after vitrectomy and intravitreal antibiotics; so, we decided to repeat vitrectomy, remove the steroid implant and fill the eye with silicon oil, and repeat intravitreal vancomycin. Vision has improved from hand movements at presentation to counting fingers at 1.5 m after second vitrectomy and final visual acuity 3 months later after silicon oil removal was 6/36.

English

Candidemia is an important cause of health care-associated bloodstream infections. Appropriate antifungal therapy is crucial to reduce morbidity and mortality. A previous randomized clinical trial compared the clinical effectiveness of caspofungin 50 mg, micafungin 100 mg (M100), and micafungin 150 mg (M150) in treating invasive candidiasis and candidemia. M100 treatment success was non-inferior to caspofungin, while M150 yielded less favourable clinical and mycological responses. Pharmacodynamic (PD) variables were explored to assess the effect of caspofungin, M100 and M150 on the following outcomes: mycological eradication, clinical success, days to eradication, recurrence, and emergent infection for cases of candidemia only from the aforementioned clinical trial. Univariate and multivariate analyses were performed to evaluate the ratio of area under the concentration curve to minimum inhibitory concentration [AUC:MIC] for the treatment arms. AUC:MIC >1500 conferred better mycological eradication, but an inverse relationship between micafungin and mycological eradication based on an AUC:MIC ≥7500 was found. M150 required more days to eradication than M100 (p<0.03) and caspofungin (p<0.02). A correlation was also noted for days to eradication with several other risk factors, including race, Candida parapsilosis, and neutropenia. Key words: Micafungin and caspofungin, echinocandins,

Clinical Predictors of T Cell Fitness for CAR T Cell Manufacturing and Efficacy in Multiple Myeloma

Introduction: The optimal clinical setting and cell product characteristics for chimeric antigen receptor (CAR) T cell therapy in multiple myeloma (MM) are uncertain. In CLL patients treated with anti-CD19 CAR T cells (CART19), prevalence of an early memory (early-mem) T cell phenotype (CD27+ CD45RO- CD8+) at time of leukapheresis was predictive of clinical response independently of other patient- or disease-specific factors and was associated with enhanced capacity for in vitro T cell expansion and CD19-responsive activation (Fraietta et al. Nat Med 2018). T cell fitness is therefore a major determinant of response to CAR T cell therapy. In an accompanying abstract (Cohen et al.), we report that higher percentage of early-mem T cells and CD4/CD8 ratio within the leukapheresis product are associated with favorable clinical response to anti-BCMA CAR T cells (CART-BCMA) in relapsed/refractory MM. Here, we compare leukapheresis samples from MM patients obtained at completion of induction therapy (post-ind) with those obtained in relapsed/refractory (rel/ref) patients for frequency of early-mem T cells, CD4/CD8 ratio, and in vitro T cell expansion. Methods: Cryopreserved leukapheresis samples were analyzed for the percentage of early-mem T cells and CD4/CD8 ratio by flow cytometry and in vitro expansion kinetics during anti-CD3/anti-CD28 bead stimulation. Post-ind samples were obtained between 2007 and 2014 from previously reported MM trials in which ex-vivo-expanded autologous T cells were infused post-ASCT to facilitate immune reconstitution (NCT01245673, NCT01426828, NCT00046852); rel/ref samples were from MM patients treated in a phase-one study of CART-BCMA (NCT02546167). Results: The post-ind cohort includes 38 patients with median age 55y (range 41-68) and prior exposure to lenalidomide (22), bortezomib (21), dexamethasone (38), cyclophosphamide (8), vincristine (2), thalidomide (8), and doxorubicin (4); median time from first systemic therapy to leukapheresis was 152 days (range 53-1886) with a median of 1 prior line of therapy (range 1-4). The rel/ref cohort included 25 patients with median age 58y (range 44-75), median 7 prior lines of therapy (range 3-13), and previously exposed to lenalidomide (25), bortezomib (25), pomalidomide (23), carfilzomib/oprozomib (24), daratumumab (19), cyclophosphamide (25), autologous SCT (23), allogeneic SCT (1), and anti-PD1 (7). Median marrow plasma cell content at leukapheresis was lower in the post-ind cohort (12.5%, range 0-80, n=37) compared to the rel/ref cohort (65%, range 0-95%). Percentage of early-mem T cells was higher in the post-ind vs rel/ref cohort (median 43.9% vs 29.0%, p=0.001, left figure). Likewise, CD4/CD8 ratio was higher in the post-ind vs rel/ref cohort (median 2.6 vs 0.87, p 2 lines of therapy prior to apheresis (n=3) compared to the rest of the cohort (n=35). Conclusion: In MM patients, frequency of the early-mem T cell phenotype, a functionally validated biomarker of fitness for CAR T cell manufacturing, was significantly higher in leukapheresis products obtained after induction therapy compared to the relapsed/refractory setting, as was CD4/CD8 ratio and magnitude of in vitro T cell expansion. This result suggests that CAR T cells for MM would yield better clinical responses at early points in the disease course, at periods of relatively low disease burden and before exposure to multiple lines of therapy. Disclosures Garfall:Novartis: Research Funding; Kite Pharma: Consultancy; Amgen: Research Funding; Bioinvent: Research Funding. Cohen:GlaxoSmithKline: Consultancy, Research Funding; Kite Pharma: Consultancy; Oncopeptides: Consultancy; Celgene: Consultancy; Novartis: Research Funding; Poseida Therapeutics, Inc.: Research Funding; Bristol Meyers Squibb: Consultancy, Research Funding; Janssen: Consultancy; Seattle Genetics: Consultancy. Fraietta:Novartis: Patents & Royalties: WO/2015/157252, WO/2016/164580, WO/2017/049166. Davis:Novartis Institutes for Biomedical Research, Inc.: Patents & Royalties. Levine:CRC Oncology: Consultancy; Brammer Bio: Consultancy; Cure Genetics: Consultancy; Incysus: Consultancy; Novartis: Consultancy, Patents & Royalties, Research Funding; Tmunity Therapeutics: Equity Ownership, Research Funding. Siegel:Novartis: Research Funding. Stadtmauer:Janssen: Consultancy; Amgen: Consultancy; Takeda: Consultancy; Celgene: Consultancy; AbbVie, Inc: Research Funding. Vogl:Karyopharm Therapeutics: Consultancy. Milone:Novartis: Patents & Royalties. June:Tmunity Therapeutics: Equity Ownership, Membership on an entity9s Board of Directors or advisory committees, Patents & Royalties, Research Funding; Tmunity Therapeutics: Equity Ownership, Membership on an entity9s Board of Directors or advisory committees, Patents & Royalties, Research Funding; Immune Design: Membership on an entity9s Board of Directors or advisory committees; Novartis Pharmaceutical Corporation: Patents & Royalties, Research Funding; Celldex: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Immune Design: Membership on an entity9s Board of Directors or advisory committees; Novartis Pharmaceutical Corporation: Patents & Royalties, Research Funding. Melenhorst:Novartis: Patents & Royalties, Research Funding; Incyte: Research Funding; Tmunity: Research Funding; Shanghai UNICAR Therapy, Inc: Consultancy; CASI Pharmaceuticals: Consultancy.

Evaluation of In Vivo CAR Transgene Levels in Relapsed/Refractory Pediatric and Young Adult ALL and Adult DLBCL Tisagenlecleucel-Treated Patients

Evaluation of In Vivo CAR Transgene Levels in Relapsed/Refractory Pediatric and Young Adult ALL and Adult DLBCL Tisagenlecleucel-Treated Patients

Tumor Treating Fields Elicit a Conditional Vulnerability in Non-Small Cell Lung Cancer Cell Lines Through the Down-Regulation of Key DNA Repair and Replication Stress Pathways that When Targeted with Chemoradiation Results in Synergistic Cell Killing

Tumor treating fields (TTFields) is a new physical modality of cancer therapy composed of low-intensity, intermediate frequency, alternating electric fields non-invasively applied to the region of the tumor. TTFields have revolutionized the treatment of recurrent and newly diagnosed glioblastoma with clinical trials ongoing for other cancers. Initial experiments revealed that a major mechanism by which TTFields kill cancer cells is through the disruption of mitosis. However, other mechanisms have now been identified. Based upon these newly described mechanisms we have examined the combination of TTFields with either cisplatin or a PARP inhibitor (Olaparib), either alone or in combination with radiation. A panel of 5 non-small cell lung cancer cell lines were exposed to TTFields for 24, 48 or 72h. Gene expression analysis, western analysis, DNA repair, DNA replication and cell survival were assessed as a function of time using combinations of TTFields, radiation, cisplatin or a PARP inhibitor. We found that the expression of the BRCA1 DNA damage repair pathway genes were significantly downregulated (P < 0.05) upon TTFields treatment which was confirmed at the protein level by western blot. TTFields treatment also slowed the repair of ionizing radiation-induced DNA damage compared to radiation alone which was evident by an increased number of DNA double strand break repair foci at any given time. TTFields alone caused the number of γH2AX foci to increase with time of exposure. The length of newly replicated DNA was reduced as a function of TTFields exposure time while the number and intensity of R-loop formations (DNA:RNA hybrid structures) increased, suggesting increased replication stress. Based upon these newly identified mechanisms of TTFields action, we hypothesized that by applying TTFields first, a conditionally vulnerable environment would develop rendering cells more susceptible to radiation, cisplatin or other agents such as PARP inhibitors that caused DNA damage, interfered with DNA repair or inhibited the resolution of stalled replication forks. We found that the effect of TTFields exposure concomitant with the PARP inhibitor Olaparib followed by radiation was synergistic compared to radiation or olaparib alone or in combination, although the degree of sensitization and synergy varied across the cell lines. We suggest that new strategies for TTFields application be considered based upon these newly identified mechanisms of action for TTFields. For example, the use of TTFields prior to radiation treatment (TTFields loading), and either prior to or concomitant with, chemotherapy agents that cause DNA damage or interfere with DNA repair or DNA replication fork resolution may result in more favorable clinical responses.

Dosis de colistina en multirresistencia: reporte de caso

Given the high resistance to antibiotics due to multiresistant bacterial infections at the hospital level, therapeutic alternatives that require the use of more potent antibiotics and higher doses should be considered. We presented the case of a 56-year-old patient with multiple surgeries and several previous antibiotic treatments. After clinical deterioration, a blood culture yield Pseudomonas aeruginosa resistant to carbapenems, treated with intravenous colistin and doripenem. The patient then developed acute renal failure, which reverts when the colistin dose decreases. Finally, the patient finishes the treatment with 10-day antibiotic adjustment and favorable clinical response.

Renovascular Hypertension and Stenosis

Renal artery stenosis (RAS) may present clinically as an incidental radiographic finding in an asymptomatic patient, or it may be the etiology of renovascular hypertension or ischemic nephropathy. Incidental RAS should be treated medically. The available clinical trial data suggest that medical management is the primary treatment for presumed renovascular hypertension. Renal artery stenting should be reserved for patients who fail medical therapy. When renal artery stenting is contemplated for presumed renovascular hypertension or ischemic nephropathy, clinical studies suggest that there are clinical predictors of outcomes that may be useful in identifying patients with a higher probability of a favorable clinical response to stenting. Clinical predictors of a favorable blood pressure response to renal artery stenting include (1) a requirement of four or more antihypertensive medications, (2) preoperative diastolic blood pressure greater than 90 mm Hg, and (3) preoperative clonidine use. The only clinical predictor of improved renal function with stenting is the rate of decline of estimated glomerular filtration rate (eGFR) in the weeks prior to stenting. Patients with a more rapid decline in eGFR have a higher probability of improved renal function after stenting compared with those with relatively stable eGFR prior to stenting. Finally, surgical renal artery revascularization remains a viable option but is usually reserved for younger, fit patients with unfavorable anatomy for stenting. Pediatric renovascular disease responds poorly to endovascular therapy and requires a surgical plan to address both renal artery stenoses and concomitant abdominal aortic coarctation if present. Renal artery stenosis in pediatric patients is best treated with reimplantation of the renal artery or interposition grafting using the autogenous internal iliac artery as a conduit. This review contains 39 references, 15 figures, and 3 tables. Key Words: chronic kidney disease, hypertension, renal artery stenosis, renovascular, stenting

Delafloxacin: A New Anti-methicillin-resistant Staphylococcus aureus Fluoroquinolone.

Delafloxacin (ABT 492) is a new fluoroquinolone available in both oral and parenteral formulations. It has recently been approved by the Food and Drug Administration for the management of acute bacterial skin and skin structure infections. When compared to combination therapy of vancomycin and aztreonam, delafloxacin was not inferior and had a favorable adverse event profile. Furthermore, its anti-methicillin-resistant Staphylococcus aureus (MRSA) activity and favorable clinical response in MRSA infections distinguishes it from other fluoroquinolones. This review focuses on the mode of action, antimicrobial activity, pharmacokinetics and pharmacodynamics, clinical indications, and safety profile of this drug. Considerations for formulary addition and its place in therapy are also discussed.

Editors' note: Infliximab for the treatment of CNS sarcoidosis: A multi-institutional series

Authors Gelfand et al. retrospectively reviewed the charts of 66 patients with CNS sarcoidosis treated with infliximab and found that most patients exhibit favorable imaging and clinical treatment responses, including some previously refractory to other immunosuppressive treatments. Commenting on the article, Dr. Avasarala had several questions, including why tumor necrosis factor (TNF)-α blockers fail in multiple sclerosis (MS) and how the extracerebral manifestations of sarcoidosis respond to infliximab. The authors explain that the pathology in MS is different from sarcoidosis, where TNF-α is important for granuloma formation and maintenance. They add that differentiating suspected inflammatory-demyelinating lesions from granulomatous pathologies in the CNS is based on clinical phenotype, MRI appearance, and clinical context. Finally, they clarify that while they did not systemically evaluate treatment responses of infliximab on other organ systems, other studies have shown a benefit. Authors Gelfand et al. retrospectively reviewed the charts of 66 patients with CNS sarcoidosis treated with infliximab and found that most patients exhibit favorable imaging and clinical treatment responses, including some previously refractory to other immunosuppressive treatments. Commenting on the article, Dr. Avasarala had several questions, including why tumor necrosis factor (TNF)-α blockers fail in multiple sclerosis (MS) and how the extracerebral manifestations of sarcoidosis respond to infliximab. The authors explain that the pathology in MS is different from sarcoidosis, where TNF-α is important for granuloma formation and maintenance. They add that differentiating suspected inflammatory-demyelinating lesions from granulomatous pathologies in the CNS is based on clinical phenotype, MRI appearance, and clinical context. Finally, they clarify that while they did not systemically evaluate treatment responses of infliximab on other organ systems, other studies have shown a benefit.